Project Summary The global decline of brain plasticity due to closure of juvenile-specific critical period is the key impedance of recovery during adult life from neurodevelopmental disorders and brain trauma. One comprehensive idea to aid functional recovery during adulthood is to reopen a second window of critical period-like globally heightened plasticity by modulating the neural circuitry of the adult brain to simulate the similar physiological events that regulate experience-dependent plasticity during critical period. Potential for such method has been revealed in recent findings using a classic murine primary visual cortex (V1) model of critical period plasticity known as ocular dominance (OD) plasticity. This proposal aims to identify novel targets to induce neuromodulatory changes in the adult visual cortex, as strategy to reactivate OD plasticity. In the adult cortex, somatostatin-expressing (SST) interneurons are known to strongly influence information processing in the adult brain. For example, cholinergic neuromodulatory inputs to the V1 can strongly augment the firing dynamics of V1 SST cells, which in turn mediates global brain-state dependent changes in visual information processing. Despite this prominent ?hub?-like function, the potential of SST cells as key target for globally enhancing plasticity in adulthood is unknown. Our preliminary study found that transient chemogenetic activation of SST cells in the adult V1 immediately following MD could reactivate OD plasticity. This implicates SST cells as a target for triggeirng the progress of global plasticity. In searching for a molecular target for controlling the dynamics of visual cortical SST cells to reactivate OD plasticity in adulthood, we turned to an endogenously SST-specific positive allosteric modulator of nicotinic signaling known as Lypd6. Strikingly, overexpression of Lypd6 in adult V1 SST cells reactivates OD plasticity through the action of the ?2 subunit containing nicotinic acetylcholine receptor (nAChR). Although our preliminary results implicate a cell- and receptor-specific mechanism of enhancement of V1 nicotinic tone by Lypd6 to elevate plasticity, it is unknown as to how exactly Lypd6 1) affects nicotinic signaling in SST cells, and whether it 2) modulates SST cell activity to 3) impact OD plasticity. Our hypothesis is that Lypd6 positively regulates OD plasticity by potentiating SST cell activity through the ?2-containing nAChR. With our experimental design that utilize in vivo viral gene transfer, optogenetics, chemogenetics, and in vivo as well as in vitro electrophysiological assays, we anticipate that our study will be the first to identify the SST cell and associated mechanisms for increasing its activity as novel targets for enhancing cortical plasticity, and in the larger perspective will shed novel strategic insights towards therapeutics and behavioral interventions towards brain disorders with enduring functional impairments such as amblyopia as well as neurodevelopmental disorders.